title: The enzyme 3-hydroxykynurenine transaminase as potential target for 1,2,4-oxadiazoles with larvicide activity against the dengue vector Aedes aegypti.
abstract: The mosquito Aedes aegypti is the vector agent responsible for the transmission of yellow fever and dengue fever viruses to over 80 million people in tropical and subtropical regions of the world. Exhaustive efforts have lead to a vaccine candidate with only 30% effectiveness against the dengue virus and failure to protect patients against the serotype 2. Hence, vector control remains the most viable route to dengue fever control programs. We have synthesized a class of 1,2,4-oxadiazole derivatives whose most biologically active compounds exhibit potent activity against Aedes aegypti larvae (ca. of 15 ppm) and low toxicity in mammals. Exposure to these larvicides results in larvae pigmentation in a manner correlated with the LC50 measurements. Structural comparisons of the 1,2,4-oxadiazole nucleus against known inhibitors of insect enzymes allowed the identification of 3-hydroxykynurenine transaminase as a potential target for these synthetic larvicides. Molecular docking calculations indicate that 1,2,4-oxadiazole compounds can bind to 3-hydroxykynurenine transaminase with similar conformation and binding energies as its crystallographic inhibitor 4-(2-aminophenyl)-4-oxobutanoic acid.
authors.affiliation: Department of Fundamental Chemistry, Federal University of Pernambuco, Recife 50740-560, Brazil.
authors.forename: Vanessa S
authors.initials: VS
authors.lastname: Oliveira
authors.forename: Cecília
authors.initials: C
authors.lastname: Pimenteira
authors.forename: Diana C B
authors.initials: DC
authors.lastname: da Silva-Alves
authors.forename: Laylla L L
authors.initials: LL
authors.lastname: Leal
authors.forename: Ricardo A W
authors.initials: RA
authors.lastname: Neves-Filho
authors.forename: Daniela M A F
authors.initials: DM
authors.lastname: Navarro
authors.forename: Geanne K N
authors.initials: GK
authors.lastname: Santos
authors.forename: Kamilla A
authors.initials: KA
authors.lastname: Dutra
authors.forename: Janaína V
authors.initials: JV
authors.lastname: dos Anjos
authors.forename: Thereza A
authors.initials: TA
authors.lastname: Soares
mesh_terms: D000330:Aedes / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D000818:Animals; D001665:Binding Sites; D007306:Insecticides; D007814:Larva / Q000187:drug effects / Q000201:enzymology; D062105:Molecular Docking Simulation; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D000637:Transaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007306:Insecticides; D010069:Oxadiazoles; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase
keywords: 4-(2-Aminophenyl)-4-oxobutanoic acid; AQKAZOMSXDNOMV-UHFFFAOYSA-N; BIASMBPERGWEBX-UHFFFAOYSA-N; BUMRHSFCLPSTJE-UHFFFAOYSA-N; CEILSLWYFCDNGC-UHFFFAOYSA-N; CFXAQQIXPRIHNU-UHFFFAOYSA-N; DEEIJRMZDVOOAA-UHFFFAOYSA-N; DPVKAFMWSAOINX-UHFFFAOYSA-N; DROIFMGZDXPPQM-UHFFFAOYSA-N; DTJLKFLJJUQICD-UHFFFAOYSA-N; FAQJQDUSWXDNGZ-UHFFFAOYSA-N; FRRHHVZZACDZPQ-UHFFFAOYSA-N; FTUATJKDOQCWME-UHFFFAOYSA-N; GBRXYEMOKYJQIM-UHFFFAOYSA-N; HBRIJIMBSGYLTA-UHFFFAOYSA-N; Insecticide; LBFLFJKKZLTGOV-UHFFFAOYSA-N; LLBGUCZJOVFEKY-UHFFFAOYSA-N; Larvae pigmentation; MZTVBDKRHBBHNR-UHFFFAOYSA-N; Malaria vector Anopheles gambiae; Molecular docking calculations; OFYZWUXIADKEIX-UHFFFAOYSA-N; PUOYKXUDPRGQQQ-UHFFFAOYSA-N; PZAHEYNFUFWABS-UHFFFAOYSA-N; RDRLTPZGMAFZNS-UHFFFAOYSA-N; ROMPPAWVATWIKR-UHFFFAOYSA-N; SUVXWDJZJAVWEA-UHFFFAOYSA-N; TUKOCDSLLJGORV-UHFFFAOYSA-N; UBSBRLFVQKHLPG-UHFFFAOYSA-N; WRFNXLGYERRRTO-UHFFFAOYSA-N; XODDCJFEBMABKW-UHFFFAOYSA-N; ZLLUXRPSSPVGOA-UHFFFAOYSA-N